Project Summary Most recent consensus statements in management of concussion emphasize the importance of early introduction of physical activity and aerobic exercise after a brief (up to 48 hours) initial rest. Since exercise may trigger or exacerbate post-concussion symptoms, even if the symptoms are absent at rest, several exercise protocols engage patients in sub-symptom threshold exercise regimens in which timing and intensity of exercise is guided by the onset and severity of self-reported symptoms. However, self-reported symptoms may not always be reliable. In fact, after a high intensity exercise, young, uninjured individuals are as likely to report an increase in ?concussion-like? symptoms as injured individuals. This highlights the need to develop objective physiologic markers that can guide the timing and intensity of exercise for optimal recovery. Cerebrovascular response to changes in arterial carbon dioxide (CO2), at rest and during exercise can address this need. The sensitivity of cerebral vasculature to changes in arterial CO2 (termed ?vasoreactivity?) is a key mechanism that helps regulate cerebral blood flow and maintain central pH at rest as well as during aerobic exercise. A derangement in this mechanism underlies, at least partly, post-concussion symptom burden: we have recently shown that patients with larger responses to CO2 at rest appear to suffer from more severe post-concussion symptoms. This has profound implications for cerebral blood flow response to aerobic exercise. In uninjured individuals, mild to moderate exercise is associated with a small increase in arterial CO2 that increases cerebral blood flow in concert with metabolism. However, after a concussion, exacerbated vascular response to CO2 may lead to increases in blood flow beyond what is required for cerebral metabolism, and this may underlie exercise- mediated symptom onset. Thus, assessment of vasoreactivity at rest can inform the optimal timing to re- introduce exercise, and monitoring cerebrovascular responses during exercise can guide its intensity to ensure optimal recovery. However, beyond anecdotal case reports, the degree to which resting vasoreactivity relates to cerebral blood flow response to exercise, and whether the latter relates to symptom onset, is unknown. The proposed research aims to address this gap in our knowledge. In a case controlled study of adolescents who recently sustained a concussion, we will determine the relation between (1) cerebral vasoreactivity at rest and cerebral blood flow response during an acute bout of sub-symptom threshold exercise and (2) exercise-induced symptom onset and cerebral blood flow response to exercise. This will allow us to define a physiologic marker that can guide optimal timing to introduce and intensity of physical exercise to mitigate the sequelae of concussion. The research team, which brings together three investigators with complementary areas of expertise and long history of successful collaboration, is uniquely poised to achieve this goal.